Treatment of wounds, particularly of more severe wounds is often very challenging. Contraction is generally regarded as a natural and essential component for wound healing. However, in many cases excessive and uncontrolled wound contraction can be observed as well as contraction induced fibrosis, which can lead to disfigurement and loss of function. Fibrosis or fibrous tissue contraction can also occur during tendon repair. This leads to shortening of tendons and/or reduction in tensile strength.
The reconstitution of tissue structural integrity in higher vertebral animals following, for example, surgical or accidental trauma, involves a broadly understood pattern of repair or wound closure. Examples of cutaneous wounds include burn wounds, neuropathic ulcers, pressure sores, venous stasis ulcers, and diabetic ulcers. Open cutaneous wounds heal routinely by a repair process that includes six major components: (1) inflammation; (2) fibroblast proliferation; (3) blood vessel proliferation; (4) connective tissue synthesis; (5) epithelialization; and (6) wound contraction. Wound healing is impaired when these components, either individually or as a whole, do not function properly. Numerous factors can affect wound healing, including malnutrition, infection, pharmacological agents (e.g., actinomycin and steroids), diabetes, and advanced age.
The reparative process begins with the recruitment of a variety of specialized cells to the effected tissue and involves extracellular matrix and basement membrane deposition, angiogenesis, selective protease activity and re-epithelialization. An important component of the healing process in adult mammals is the stimulation of fibroblasts to generate the extracellular matrix. This extracellular matrix constitutes a major component of the connective tissue which develops to repair a wound area. The repair process, however, is not perfect and the connective tissue is often fibrous in nature and commonly forms into a connective tissue scar (a process known as fibrosis). Scars are composed of a connective tissue which is predominately a matrix of collagen types 1 and 3 and fibronectin. The scar may consist of collagen fibers in an abnormal organization (as seen in scars of the skin) or it may be an abnormal accumulation of connective tissue (as seen in scars of the central nervous system). Most scars consist of abnormally organized collagen and also excess collagen.
A cutaneous or dermal scar may be defined as the macroscopic disturbance of normal skin structure and function arising as a consequence of wound repair.
In man, in the skin, scars may be depressed below the surface or elevated above the surface of the skin. Hypertrophic scars are a more severe form of normal scarring and are elevated above the normal surface of the skin and contain excessive collagen arranged in an abnormal pattern. A keloid is another form of pathological scarring which is not only elevated above the surface of the skin but also extends beyond the boundaries of the original injury. In a keloid there is excessive connective tissue which is organized in an abnormal fashion predominately in whirls of collagenous tissue. Examples of such situations are scars of the skin where excessive scarring may be detrimental to tissue function and particularly when scar contracture occurs (for instance skin burns and wounds which impair flexibility of a joint). In the skin, hypertrophic or keloid scars can cause functional and cosmetic impairment and there is a need to prevent their occurrence. Scarring resulting from the use of skin grafts, in both donor and recipient sites, and from the application of artificial skin, can also be problematic and needs to be minimized or prevented.
Various agents, wound dressings, lyophilized pig skin, composites and methods have been proposed in the art for applications in the field of wound treatment. Wound dressings and ointment gauzes are generally used as therapy for a skin defect reaching to an upper layer of dermis, such as a superficial dermal burn. When a skin defect reaches to a lower layer of dermis, such as a deep dermal burn, a dermal burn or a decubitus in at least the second grade, self-reconstruction in a cutaneous tissue by proliferation of epidermal cells is usually problematic. These defects are typically treated by debriding a slough or an abnormal granulation tissue, reconstructing a normal granulation tissue by covering the defect with an allogeneic skin, xenogeneic skin, artificial silicon skin, skin replacement products, wound dressings or the like, and reconstructing a skin by performing skin graft. Skin grafts have been used in general to resurface superficial defects of many kinds.
A split-thickness graft (STSG) contains epidermis and a variable amount of dermis. A full-thickness graft (FTSG) includes all of the dermis and the epidermis. The graft may be an autograph taken from another part of the same individual, an isograph taken from a genetically identical donor, an allograph taken from another individual of the same species or a xenograph taken from an individual of different species. In the treatment of deep burn wounds that require excision, autologous split-thickness skin grafting (STSG) is the standard treatment today. The amount of dermis included with the graft determines both the likelihood of survival and the level of contracture.
Treatment with skin grafts, such as STSGs is, however, not without problems. In ideal conditions, having a healthy wound bed and in the absence of infections, a STSG will adhere or “take” well, however, in many cases the conditions may be far from ideal. For example the wound bed may bleed, be infected, it may contain wound excretion, epithelisation may be weakened, due to shear force, or the thickness of the STSG is not suitable, which all may significantly impair the “take” and healing process.
A skin graft begins to shrink immediately after harvest. As a result of primary contraction the skin graft may lose from about 40% to about 10% of its original area. After transfer to a recipient site, the skin graft will shrink as it heals; this is understood as secondary contraction. FTSGs tend to remain the same size after significant primary contraction, but STSGs contract whenever the circumstances allow. STSGs have greater likelihood of secondary contracture, and particularly thinner STSGs tend to shrink considerably and pigment abnormally. Dermis has contraction-inhibiting effect and the greater the proportion of dermis in the graft, the greater the inhibition and the less the graft will contract. Thus high contraction rates are typically associated particularly with thin STSGs.
With the STSGs dermal appendages, such as hair follicles largely remain intact at the donor site permitting stem cell activation and epidermis resurfacing from these niches. The graft donor sites thus typically heal within about three weeks to permit re-harvesting of the same site that is essential in the treatment of large burns. For covering large wound areas STSGs can be meshed to enable graft expansion, usually in a 1:1.5 to 1:6 ratio. The interstices of the meshed graft heal by epithelial migration from the graft's edges.
Graft and wound contraction always occurs primarily at the outset and the process can continue for many months after the wound has healed. Ensuing fibrotic scar contracture can lead to restriction of the patient's movements as well as a poor cosmetic result. All healed burns as well as skin grafted burns therefore require intensive scar therapy after the acute phase in an attempt to prevent scar formation and contracture problems.
Contraction and fibrosis may also result from rejection occurring particularly in connection with the use of allogeneic skin or xenogeneic skin grafts.
In a similar manner contraction occurs also in connection with the treatment and healing of mucous membranes. Particularly problematic areas are mucous membranes, skin areas with very thin epithelium, such as eyelids, and large burn wounds.
There is still at present neither a truly effective treatment available, nor a plausible method for the control and/or prevention of contraction. Additionally, the extent of fibrosis and contraction is unpredictable and in the more difficult cases reoperation and/or surgical release or removal of fibrotic tissue, as well as a further STSG transplantation may be required.
Whilst the above considerations mainly apply to contraction and fibrosis development in man, it will be appreciated that contraction and fibrosis can also be problematic in other animals, particularly in the veterinary field in the treatment of animals like domestic animals (e.g. horses, cattle, dogs, cats). Abdominal wounds are an example of one major reason for having to put down race horses.
Some pharmacological agents, such as beta-aminopropionitrilefumarate (beta-APN or BAPN-F), are used for inhibiting collagen crosslinking in veterinary medicine. There are also a number of post-scarring agents that attempt to treat the scar once formed.
Microbially produced cellulose gel, modified by bonding chemically or physically an animal cell adhesive protein to the cellulose, useful particularly in sheet form as artificial skin or vulnerable cover, is suggested in U.S. Pat. No. 5,558,861.
WO 2007/027849 describes the use of microbial nanocellulose as a substrate in wound healing systems, suitably in wound dressings. Said microbial nanocellulose is particularly multi-ribbon cellulose produced by specific Gluconoacetobacter strains. The dressing may additionally comprise one or more active substances, such as biologically active peptides, proteins, small molecules, lipids etc., and it may also be formed into a suture, sheet, compress, bandage, band, prosthesis, fiber, woven fiber, bead, strip or gauze.
US 2007/0231271 relates to a topical composition in gel form, comprising bacterial cellulose paste, gel-forming cellulose derivative and propylene glycol, for the treatment of epithelial lesions, such as burns, abrasions, cuts, post-surgical wounds and ulcers. After application and drying of the composition a mechanical barrier, such as a film or membrane is formed protecting the injured area.
WO 2012107648 relates to external use of microfibrillated cellulose, in the form of aqueous gel, ointment foam etc., for the treatment of skin inflammations, atopic dermatitis, psoriasis and skin burns in general.
Publication US 2012231038 describes a biocompatible cellulose hydrogel membrane for wound treatment, particularly for ocular wounds. Said cellulose hydrogel membrane comprises cellulose, microcrystalline cellulose or microbial cellulose, obtained by activating cellulose, dissolving the activated cellulose and allowing the obtained solution to gel. Said hydrogel membrane has sufficient tensile strength and tear strength for wound treatment applications.
Despite the ongoing research and development, there is still a need to provide improved agents, compositions and methods for the prevention of contraction in connection with wound treatment, wound healing and tissue repair. Further, there is a need for methods, agents and compositions for the prevention the development of fibrosis.